SummaryBackground18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016.MethodsUsing all available data sources, the India State-level Disease Burden Initiative estimated burden (metrics were deaths, disability-adjusted life-years [DALYs], prevalence, incidence, and life expectancy) from 333 disease conditions and injuries and 84 risk factors for each state of India from 1990 to 2016 as part of GBD 2016. We divided the states of India into four epidemiological transition level (ETL) groups on the basis of the ratio of DALYs from communicable, maternal, neonatal, and nutritional diseases (CMNNDs) to those from non-communicable diseases (NCDs) and injuries combined in 2016. We assessed variations in the burden of diseases and risk factors between ETL state groups and between states to inform a more specific health-system response in the states and for India as a whole.FindingsDALYs due to NCDs and injuries exceeded those due to CMNNDs in 2003 for India, but this transition had a range of 24 years for the four ETL state groups. The age-standardised DALY rate dropped by 36·2% in India from 1990 to 2016. The numbers of DALYs and DALY rates dropped substantially for most CMNNDs between 1990 and 2016 across all ETL groups, but rates of reduction for CMNNDs were slowest in the low ETL state group. By contrast, numbers of DALYs increased substantially for NCDs in all ETL state groups, and increased significantly for injuries in all ETL state groups except the highest. The all-age prevalence of most leading NCDs increased substantially in India from 1990 to 2016, and a modest decrease was recorded in the age-standardised NCD DALY rates. The major risk factors for NCDs, including high systolic blood pressure, high fasting plasma glucose, high total cholesterol, and high body-mass index, increased from 1990 to 2016, with generally higher levels in higher ETL states; ambient air pollution also increased and was highest in the low ETL group. The incidence rate of the leading causes of injuries also increased from 1990 to 2016. The five leading individual causes of DALYs in India in 2016 were ischaemic heart disease, chronic obstructive pulmonary disease, diarrhoeal diseases, lower respiratory infections, and cerebrovascular disease; and the five leading risk factors for DALYs in 2016 were child and maternal malnutrition, air pollution, dietary risks, high systolic blood pressure, and high fasting plasma glucose. Behind these broad trends many variations existed between the ETL state groups and between states within the ETL groups. Of the ten le...

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N-Myristoyltransferase (NMT) transfers myristate to an amino-terminal glycine of many eukaryotic proteins. In yeast, worms, and flies, this enzyme is essential for viability of the organism. Humans and mice possess two distinct but structurally similar enzymes, NMT1 and NMT2. These two enzymes have similar peptide specificities, but no one has examined the functional importance of the enzymes in vivo. To address this issue, we performed both genetic and biochemical studies. Northern blots with RNA from adult mice and in situ hybridization studies of day 13.5 embryos revealed widespread expression of both Nmt1 and Nmt2. To determine whether the two enzymes are functionally redundant, we generated Nmt1-deficient mice carrying a ␤-galactosidase marker gene. ␤-Galactosidase staining of tissues from heterozygous Nmt1-deficient (Nmt1؉/؊) mice and embryos confirmed widespread expression of Nmt1. Intercrosses of Nmt1؉/؊ mice yielded no viable homozygotes (Nmt1؊/؊), and heterozygotes were born at a less than predicted frequency. Nmt1؊/؊ embryos died between embryonic days 3.5 and 7.5. Northern blots revealed lower levels of Nmt2 expression in early development than at later time points, a potential explanation for the demise of Nmt1؊/؊ embryos. To explore this concept, we generated Nmt1؊/؊ embryonic stem (ES) cells. The Nmt2 mRNA could be detected in Nmt1؊/؊ ES cells, but the total NMT activity levels were reduced by ϳ95%, suggesting that Nmt2 contributes little to total enzyme activity levels in these early embryo cells. The Nmt1؊/؊ ES cells were functionally abnormal; they yielded small embryoid bodies in in vitro differentiation experiments and did not contribute normally to organogenesis in chimeric mice. We conclude that Nmt1 is not essential for the viability of mammalian cells but is required for development, likely because it is the principal N-myristoyltransferase in early embryogenesis.

Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is one of the key enzymes involved in the complex interactions between the cyclic nucleotide and Ca2+ second messenger systems. Currently, three genes encode PDE1, and alternate splicing of these genes gives rise to functionally different isozymes which exhibit distinct catalytic and regulatory properties. Some isozymes have similar kinetic and immunological properties but are differentially regulated by Ca2+ and calmodulin. These isozymes also differ in their mechanism of regulation by phosphorylation. Analysis of various regulatory reactions involving Ca2+ and cyclic adenosine monophosphate (cAMP) has revealed the importance of the time dependence of these reactions during cell activation; however, no measurement is available for the time of occurrence of specific regulatory reactions. cAMP-signalling systems provide a pivotal centre for achieving crosstalk regulation by various signalling pathways. It has been proposed that polypeptide sequences enriched in proline (P), glutamate (E), serine (S) and threonine (T), known as PEST motifs, serve as putative intramolecular signals for rapid proteolytic degradation by calpains. Calpains are Ca(2+)-dependent cysteine proteases that regulate various enzymes, transcription factors and structural proteins through limited proteolysis. Isozyme PDE1A2 has a PEST motif and acts as a substrate for m-calpain. In this paper, we have described PDE1A2 regulation by calpains and its physiological implications. cAMP is an important component of the signal transduction pathway and plays an integral role in various physiological processes such as gene transcription, various neuronal functions, cardiac muscle contraction, vascular relaxation, cell proliferation and a host of other functions. It is important to identify the cellular processes where PDE isoform(s) and cAMP response are altered. This will lead to better understanding of the pathology of disease states and development of novel therapeutics. The different PDE1 isozymes, although similar in kinetic properties, can be distinguished by various pharmacological agents. Our recent understanding of the role of PDE1 inhibitors such as ginseng, dihydropy-ridine antagonists and antiparkinsonian agents are described in this review. The exact function of PDE1 isozymes in various pathophysiological processes is not clear because most of the studies have been carried out in vitro; therefore, it is essential that further research be directed to in vivo studies.

This study demonstrates for the first time that N-myristoyltransferase activity is higher in colonic epithelial neoplasms than in normal-appearing colonic tissue and that an increase in N-myristoyltransferase activity appears at an early stage in colonic carcinogenesis.

Purpose Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been demonstrated to contribute to melanoma tumorigenesis, including constitutive activation of MAP kinase, Akt and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, tris (dibenzylideneacetone) dipalladium (Tris DBA), demonstrated significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA Experimental Design Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. In order to find the mechanism of action of Tris DBA, we performed Western Blot analysis and gene array analysis. The ability of Tris DBA to block tumor growth in vivo was assessed. Results (Tris DBA), has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of MAP kinase, Akt, Stat-3 and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase 1 (NMT-1), which is required for optimal activity of membrane based signaling molecules. Tris DBA demonstrated potent antitumor activity in vivo against melanoma. Conclusion Tris DBA is thus a novel inhibitor of NMT-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.

An effort has been made to develop concrete compressive strength prediction models with the help of two emerging data mining techniques, namely, Artificial Neural Networks (ANNs) and Genetic Programming (GP). The data for analysis and model development was collected at 28-, 56-, and 91-day curing periods through experiments conducted in the laboratory under standard controlled conditions. The developed models have also been tested on in situ concrete data taken from literature. A comparison of the prediction results obtained using both the models is presented and it can be inferred that the ANN model with the training function Levenberg-Marquardt (LM) for the prediction of concrete compressive strength is the best prediction tool.

Colorectal cancer (CRC) is the third most common cause of cancer death in the Western world. Calcineurin (CaN), a Ca2+/calmodulin (CaM)-dependent protein phosphatase, is important for Ca2+-mediated signal transduction. The main objective of this study is to examine the potential role of Ca2+/CaM-dependent protein phosphatase in both normal and in invasive tumor components of human samples. In this study, we carried out 45 cases of CaN activity, 13 cases of CaN protein expression by Western blot analysis, and 6 cases for immunohistochemical analysis in both normal and invasive tumor components of human samples. Immunohistochemical analysis revealed that strong cytoplasmic staining of varying intensity was observed in colon tumors of all patients compared to normal mucosa. In addition, Western blot analysis revealed a prominent overexpressed immunoreactive band with an apparent molecular mass of 60 kDa catalytic alpha subunit (CaN A) as well as CaN Aalpha and beta in colon tumor samples. Elevated CaN protein expression appears to be a possible link between Ca2+ signaling and oncogenic processes.